foods Review Cow’s Milk Processing—Friend or Foe in Food Allergy? Sabine Geiselhart †, Aleksandra Podzhilkova † and Karin Hoffmann-Sommergruber * Department of Pathophysiology and Allergy Research, Medical University of Vienna, 1090 Vienna, Austria; [email protected] (S.G.); [email protected] (A.P.) * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Cow’s milk (CM) is an integral part of our daily diet starting in infancy and continuing throughout our lifetime. Its composition is rich in proteins with a high nutritional value, bioactive components, milk minerals including calcium, and a range of immunoactive substances. However, cow’s milk can also induce a range of immune-mediated diseases including non-IgE-mediated food allergies and IgE-mediated food allergies. Cow’s milk allergens have been identified and char- acterized and the most relevant ones can be assigned to both, the whey and casein fraction. For preservation a range of processing methods are applied to make cow’s milk and dairy products safe for consumers. However, these methods affect milk components and thus alter the overall immuno- genic activity of cow’s milk. This review summarizes the current knowledge on cow’s milk allergens and immunoactive substances and the impact of the different processes up- or downregulating the immunogenicity of the respective proteins. It highlights the gaps of knowledge of the related disease mechanisms and the still unidentified beneficial immunomodulating compounds of cow’s milk. Keywords: cow’s milk allergens; whey; casein; food processing; IgE-mediated food allergy Citation: Geiselhart, S.; Podzhilkova, A.; Hoffmann-Sommergruber, K. Cow’s Milk Processing—Friend or 1. Introduction Foe in Food Allergy?. Foods 2021, 10, Milk consumption by humans has been tightly connected with settledness and agricul- 572. https://doi.org/10.3390/ ture from the very beginning. Recent findings provide evidence that humans were already foods10030572 drinking milk at least 6000 years ago [1]. Collecting, processing, and consuming milk from animals enabled one of the most profound revolutions in human diet and for centuries, Academic Editor: Michelle Colgrave cow’s milk has been an integral part of our diet. Animal milk is a renewable food source rich in proteins, fat, and micronutrients. For centuries, it has been used as alternative for Received: 7 February 2021 breast milk and enabled early weaning with significant demographic implications. Since Accepted: 2 March 2021 then strategies for preserving milk have been developed and continuously improved—for Published: 9 March 2021 example, the generation of yogurt, butter, and cheese are old traditional methods. Nowa- days, highly refined technologies are in place to offer safe and convenient consumption. Publisher’s Note: MDPI stays neutral However, these methods may also have a negative effect on the micronutrients which are with regard to jurisdictional claims in present in natural milk products. Furthermore, the food and pharmaceuticals industries published maps and institutional affil- use individual milk components in many different applications. iations. It is also known that milk can induce immune-mediated diseases. Although milk is regarded as a healthy food with high nutritional value it can be harmful to some individuals with a predisposition to develop immune-mediated adverse reactions to foods. Food allergy prevalence rates have increased, including cow’s milk allergy. Changes in lifestyle and Copyright: © 2021 by the authors. dietary habits may account for this, since milk consumption is no longer only regarded as Licensee MDPI, Basel, Switzerland. part of a healthy diet for infants and children—nowadays it is consumed throughout one’s This article is an open access article lifetime. Moreover, exposure to milk-derived components (milk protein, sugars, lipids) has distributed under the terms and increased since they are present in a range of highly processed convenience food products, conditions of the Creative Commons cosmetics, and pharmaceutical drugs. Attribution (CC BY) license (https:// This review is dedicated to summarizing the current knowledge of milk allergens and creativecommons.org/licenses/by/ the food processing techniques which may modulate their immunogenicity. 4.0/). Foods 2021, 10, 572. https://doi.org/10.3390/foods10030572 https://www.mdpi.com/journal/foods Foods 2021, 10, 572 2 of 17 2. Brief Overview on Immune-Mediated Diseases Caused by Milk Proteins 2.1. IgE- and Cell-Mediated Allergies Adverse reactions to foods can induce a variety of immune-mediated reactions, rang- ing from mild to severe symptoms, some of which persist throughout one’s lifetime while others resolve. For a restricted number of food-related diseases the causative foods are known, including milk and dairy products. After birth newborns are usually breast- fed and in due course exposed to cow’s milk and/or related milk sources, representing one of the earliest encounters with foreign (nonself) dietary antigens. Therefore, most immune-mediated diseases caused by milk intake start early in life and resolve within early childhood, while in adolescence and adulthood only a comparatively reduced number of diseases persist or develop. Adverse immune reactions to foods can be assigned to IgE-mediated, mixed IgE- and cell-mediated, and cell-mediated groups based on the underlying mechanisms [2]. Currently, food protein-induced enterocolitis syndrome (FPIES), food protein-induced enteropathy (FPE), and food protein-induced allergic proctocolitis (FPIAP) are listed under “non-IgE-mediated gastrointestinal food allergic disorders (non IgE-GI-FAs)” [3]. These diseases start early in infancy, are relatively rare and with a good prognosis resolving after 1–3 years. The majority of patients experience symptoms until the age of 5 years [3]. For these diseases cow’s milk proteins seem to be a relevant trigger, although other food sources such as soy, wheat, and egg have been reported. For all these foods no specific immunogenic proteins have been identified so far; it is generally accepted that the cow’s milk protein fraction per se is causative. Food protein-induced allergic proctocolitis (FPIAP) is a cell-mediated immune disease caused by cow’s milk, soy, egg, and wheat in the maternal diet when breastfed, and milk and soy formulas [3]. Usually, the symptoms are bloody intermittent stools in otherwise healthy and thriving babies [3]. Although the underlying pathomechanism is not well understood, increased eosinophils have been identified in intestinal endoscopies. Diagnosis is based on characteristic symptoms and elimination diet for diagnostic purposes can be performed. After 4–8 weeks, reintroduction of the causative foods is possible based on symptom amelioration. Usually FPIAP resolves after some months. Food protein-induced enterocolitis syndrome (FPIES) starts within the first year of life. The clinical picture includes malabsorption, anemia, diarrhea, and vomiting and can lead to failure to thrive. Similarly to FPIAP the pathogenesis of FPIES is not well understood but studies provided evidence of T cells secreting inflammatory cytokines and the role of neuroendocrine pathways in this disease was discussed. Moreover, neutrophilia and thrombocytosis are frequently identified in patients [4]. Milk was in most cases the causative food and children resolving the disease within 5 years had no detectable milk specific IgE antibodies, whereas patients with milk positive IgE had consistent milk adverse reactions [5]. Food protein enteropathy (FPE) usually presents with chronic diarrhea which does not result in severe dehydration. Cow’s milk protein is also the most important food trigger for this disease. The histology of FPE patients provides damage to the villi, and the presence of eosinophils and cow’s milk-specific Th2 cells and sometimes local IgE production. In summary, non-IgE-GI-FAs share the same food(s) that trigger/induce symptoms, their individual pathomechanisms are not well understood and a potential risk of under- diagnosed cases is possible. However, the majority of cases experience tolerance induction within the first year [6]. The question remains whether cow’s milk proteins are the causative trigger of the diseases mentioned above or whether it is the first encounter between dietary proteins and an as yet immature digestive tract which causes the symptoms. Another immune-mediated disease that is triggered by certain foods including milk is eosinophilic esophagitis (EoE). This disease is diagnosed by a high number of eosinophilic infiltrates and dysfunction of the esophagus resulting in difficulties swallowing food and food impaction. This fairly recently identified disease has been diagnosed in both children and adults. Although food-specific IgE antibodies have been determined in a subgroup of Foods 2021, 10, 572 3 of 17 patients, it remains to be established if the presence of IgE antibodies is an epiphenomenon or linked with the pathomechanism which is still poorly understood for EoE [7]. 2.2. IgE-Mediated Milk Allergy 2.2.1. Prevalence Cow’s milk is one of the first nutritional sources for infants and in atopic individuals IgE-mediated allergic symptoms can be diagnosed soon after first exposure. Symptoms range from acute cutaneous reactions e.g., urticaria, atopic dermatitis, immediate breathing problems, gastrointestinal problems, and asthma attacks up to anaphylactic reactions. In a systematic review prevalence rates of